Antidepressant Effects of (S)-Ketamine through a Reduction of Hyperpolarization-Activated Current I_h

Compelling evidence suggests that a single sub-anesthetic dose of (R,S)-ketamine exerts rapid and robust antidepressant effects. However, the cellular mechanisms underlying the antidepressant effects of (R,S)-ketamine remain unclear. Here, we show that (S)-ketamine reduced dendritic but not somatic hyperpolarization-activated current I_h of dorsal CA1 neurons in unstressed rats, whereas (S)-ketamine decreased both somatic and dendritic I_h in chronic unpredictable stress (CUS) rats. The reduction of I_h by (S)-ketamine was independent of NMDA receptors, barium-sensitive conductances, and cAMP-dependent signaling pathways in both unstressed and CUS groups. (S)-ketamine pretreatment before the onset of depression prevented CUS-induced behavioral phenotypes and neuropathological changes of dorsal CA1 neurons. Finally, in vivo infusion of thapsigargin-induced anxiogenic- and anhedonic-like behaviors and upregulation of functional I_h, but these were reversed by (S)-ketamine. Our results suggest that (S)-ketamine reduces or prevents I_h from being increased following CUS, which contributes to the rapid antidepressant effects and resiliency to CUS.